US9067896B2 - Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl) -phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof - Google Patents

Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl) -phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof Download PDF

Info

Publication number
US9067896B2
US9067896B2 US13/514,308 US201013514308A US9067896B2 US 9067896 B2 US9067896 B2 US 9067896B2 US 201013514308 A US201013514308 A US 201013514308A US 9067896 B2 US9067896 B2 US 9067896B2
Authority
US
United States
Prior art keywords
free base
water
phosphate salt
anhydrous
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US13/514,308
Other languages
English (en)
Other versions
US20120245182A1 (en
Inventor
Joerg Berghausen
Prasad K Kapa
Joseph McKenna
Joel Slade
Raeann Wu
Zhengming Du
Frank Stowasswer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=43983750&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US9067896(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Novartis AG filed Critical Novartis AG
Priority to US13/514,308 priority Critical patent/US9067896B2/en
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KAPA, PRASAD KOTESWARA, BERGHAUSEN, JOERG, STOWASSER, FRANK, SLADE, JOEL, DU, ZHENGMING, MCKENNA, JOSEPH, WU, RAEANN
Publication of US20120245182A1 publication Critical patent/US20120245182A1/en
Application granted granted Critical
Publication of US9067896B2 publication Critical patent/US9067896B2/en
Active legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present technology relates to anhydrous polymorphs, hydrated polymorphs and amorphous forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl ⁇ -1-methyl-urea, its salts, methods for preparing them, compositions containing them, and methods of treatment employing them.
  • the compound of Formula I is a protein kinase inhibitor and is useful in the treatment of proliferative diseases mediated by protein kinases.
  • the compound of Formula I inhibits FGFR1, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret kinases. It is therefore useful in the treatment of cancers including AML, melanocytic neoplasia, breast cancer, colon cancer, lung cancer (especially small-cell lung cancer), cancer of the prostate or Kaposi's sarcoma.
  • Crystalline forms occur where the same composition of matter crystallizes in a different lattice arrangement resulting in different thermodynamic properties and stabilities specific to the particular crystalline form. Crystalline forms may also include different hydrates or solvates of the same compound. In deciding which form is preferable, the numerous properties of the forms are compared and the preferred form chosen based on the many physical property variables.
  • crystal and amorphous forms of the compound of Formula I compositions including the crystal and amorphous forms, and methods of preparing the crystal and amorphous forms and compositions.
  • the present technology further provides methods of using the crystal or amorphous forms of compounds of Formula I and compositions thereof to treat various diseases, including but not limited to, those that can be prevented, inhibited or ameliorated by inhibition of kinase activity selected from FGFR1, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret kinases.
  • FIGS. 1A-E XRPD of free base ( FIG. 1A ) of the compound of Formula I and its phosphate salts: form A ( FIG. 1B ); and form B ( FIG. 1C ), the free base monohydrate ( FIG. 1D ), and the hydrochloride dihydrate ( FIG. 1E ).
  • FIGS. 2A and 2B DSC thermograms for the compound of Formula I as the anhydrous free base ( FIG. 2A and as the phosphate salt (form A, FIG. 2B ).
  • FIGS. 3A-3C TGA thermograms for the compound of Formula I as the anhydrous free base ( FIG. 3A ), as the phosphate salt (form A, FIG. 3B ), and as the hydrochloride salt (dihydrate, FIG. 3C ).
  • FIGS. 4A-4C Sorption-desorption isotherms for the compound of Formula I as the anhydrous free base ( FIG. 4A ), as the phosphate salt (form A, FIG. 4B ) and as the monohydrate free base ( FIG. 4C ) collected by DVS at 25° C.
  • FIGS. 5A and 5B SEM micrographs of the compound of Formula I as the crystalline free base ( FIG. 5A ) and as the phosphate salt (form A, FIG. 5B ).
  • FIG. 6 FT-IR-spectrum of the phosphate salt (form A) of the compound of Formula I.
  • FIG. 7 DSC and TGA thermograms of the free base monohydrate.
  • FIGS. 8A and 8B Raman spectra of the compound of Formula I as the anhydrous free base ( FIG. 8A ) and as the monohydrate of the free base ( FIG. 8B ).
  • FIG. 9 Single crystal X-ray structure of the elementary cell of the free base monohydrate form of the compound of Formula I.
  • the present technology provides anhydrous and hydrated crystalline forms of the compound of Formula I (the free base):
  • the present technology provides an anhydrous crystalline form of the free base having an X-ray powder diffraction pattern comprising a characteristic peak, in terms of 2 ⁇ , at about 12°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 10.5°, about 15.2°, about 19.5°, and about 21.0°.
  • the X-ray powder diffraction pattern for an anhydrous form of the free base may comprise one, two, three, four, or five characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 10.5°, about 12.0°, about 15.2°, about 19.5°, and about 21.0°.
  • the X-ray powder diffraction pattern may further include one, two or three additional characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 11.9°, about 21.3°, and about 22.6°.
  • the anhydrous crystalline form of the free base has an X-ray powder diffraction pattern substantially as shown in FIG. 1A .
  • the terms “about” and “substantially” indicate, with respect to values of 2 ⁇ , that such values for individual peaks can vary by ⁇ 0.4°. In some embodiments, the values of 2 ⁇ for individual peaks can vary by ⁇ 0.2°.
  • the anhydrous crystalline form of the free base may be characterized thermally.
  • the anhydrous crystalline form of the free base has a differential scanning calorimetry (DSC) thermogram showing an onset of an endotherm at about 217° C.
  • the anhydrous crystalline form of the free base has a differential scanning calorimetry thermogram substantially as shown in FIG. 2A .
  • the terms “about” and “substantially” indicate with respect to features such as endotherms, exotherms, baseline shifts, etc., that their values can vary ⁇ 2° C.
  • variation in the temperatures observed will depend upon the rate of temperature change as well as sample preparation technique and the particular instrument employed. Thus, the values reported herein relating to DSC thermograms can vary ⁇ 4° C.
  • the anhydrous crystalline form of the free base may also be characterized by Raman spectroscopy.
  • the anhydrous crystalline form of the free base exhibits characteristic Raman peaks at about 2950, about 1619, about 1539, about 1297, about 1233, about 1191, and about 998 cm ⁇ 1 .
  • the anhydrous crystalline form of the free base exhibits one or more further characteristic Raman peaks at about 3067, about 2927, about 2828, about 1690, about 1585, about 1458, about 1385, about 1358, about 1098, about 1062, about 819, about 778, about 695, about 668, about 637, about 498, about 468, and about 420 cm ⁇ 1 .
  • the anhydrous crystalline form of the free base has a Raman spectrum substantially as shown in FIG. 8A .
  • the terms “about” and “substantially” indicate, with respect to wave number values, that such values for individual peaks can vary by ⁇ 2 cm ⁇ 1 .
  • the present technology provides a crystalline monohydrate of the free base having an X-ray powder diffraction pattern comprising a characteristic peak, in terms of 2 ⁇ , at about 20.3°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 21.2° and 19°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 4.7°, about 9.4°, and about 11.0°.
  • the X-ray powder diffraction pattern for a monohydrate form of the free base may comprise one, two, three, four, five, or six characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 4.7°, about 9.4°, about 11.0°, about 18.8°, about 20.3°, and about 21.2°.
  • the X-ray powder diffraction pattern for a monohydrate form of the free base may additionally include one, two, three, four, five, six or seven characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 11.8°, about 15.3°, about 16.2°, about 19.1°, about 22.3°, about 22.8°, and about 25.3°.
  • the crystalline monohydrate form of the free base has an X-ray powder diffraction pattern substantially as shown in FIG. 1D .
  • the crystalline monohydrate form of the free base may be characterized thermally.
  • the crystalline monohydrate form of the free base has a DSC thermogram showing an onset of an endotherm at about 211° C.
  • the crystalline monohydrate form of the free base has a DSC thermogram and/or a TGA thermogram substantially as shown in FIG. 7 .
  • the monohydrate crystalline form of the free base may also be characterized by Raman spectroscopy.
  • the anhydrous crystalline form of the free base exhibits characteristic Raman peaks at about 2957, about 2831, about 1618, about 1511, about 1465, about 1361, about 1229, about 1186, and about 994 cm ⁇ 1 .
  • the anhydrous crystalline form of the free base exhibits further characteristic Raman peaks at about 1580, about 1415, about 1312, about 1284, about 1184, about 1057, about 854, about 721, about 661, and about 624 cm ⁇ 1 .
  • the monohydrate crystalline form of the free base has a Raman spectrum substantially as shown in FIG. 8B .
  • the present technology provides an anhydrous crystalline monophosphoric acid salt (or phosphate) of the compound of Formula I:
  • the anhydrous crystalline monophosphoric acid salt is of form A which has an X-ray powder diffraction pattern comprising a characteristic peak, in terms of 2 ⁇ , at about 15°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 13.7°, about 16.8°, about 21.3° and about 22.4°.
  • the X-ray powder diffraction pattern further comprises one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 9.2°, about 9.6°, about 18.7°, about 20.0°, about 22.9°, and about 27.2°.
  • the anhydrous crystalline form (form A) of a monophosphoric acid salt (or the phosphate salt) of the compound of Formula I has an X-ray powder diffraction pattern comprising at least three characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 13.7°, about 15°, about 16.8°, about 21.3° and about 22.4°.
  • the X-ray powder diffraction pattern for form A of the phosphate salt may comprise one, two, three, four, five, six, seven, eight, nine, ten or eleven characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 9.2°, about 9.6°, about 13.7°, about 15°, about 16.8°, about 18.7°, about 20.0°, about 21.3° and about 22.4°, about 22.9°, and about 27.2°.
  • the anhydrous crystalline form (form A) of the phosphate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 1B .
  • the anhydrous crystalline form of the phosphate salt (form A) may be characterized thermally.
  • the anhydrous crystalline form of the phosphate salt (form A) has a differential scanning calorimetry thermogram showing an onset of an endotherm at about 184° C.
  • the anhydrous crystalline form of the phosphate salt (form A) has a differential scanning calorimetry thermogram substantially as shown in FIG. 2B .
  • the present technology provides an anhydrous crystalline monophosphoric acid salt of form B which has an X-ray powder diffraction pattern comprising one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 9.3°, about 12.5°, about 13.4°, about 15.8°, and about 17°.
  • the form B of the phosphate salt has an X-ray powder diffraction pattern substantially as shown in FIG. 1C .
  • the present technology provides the amorphous form of the monophosphoric acid salt of the compound of Formula I:
  • the XRPD of the amorphous form of the monophosphoric acid salt of the compound of Formula I does not display characteristic peaks. No apparent glass transition was observed by DSC for the amorphous form, but during TGA, the sample started to decompose at about 115° C., much lower than the form A of the crystalline phosphate salt.
  • the present technology provides the hydrochloric acid salt (or the hydrochloride) of the compound of Formula I:
  • the hydrochloride salt is the crystalline dihydrate.
  • the dihydrate may have an X-ray powder diffraction pattern comprising one or more characteristic peaks, in terms of 2 ⁇ , selected from peaks at about 10.9°, about 12.1°, about 14.8°, about 20.5°, about 22°, and about 25.1°.
  • the hydrochloride salt has an X-ray powder diffraction pattern substantially as shown in FIG. 1E .
  • XRPD single crystal X-ray diffraction
  • DSC dynamic vapor sorption
  • DRS dynamic vapor sorption
  • crystal morphology solid state nuclear magnetic resonance
  • Raman scattering infrared (IR) spectroscopy
  • the present technology provides a method of making the anhydrous crystalline form of the phosphate salt of form A, comprising contacting a suspension of a compound of Formula I (the free base):
  • the suspension of the compound of Formula I comprises isopropanol.
  • the method further comprises crystallizing the anhydrous crystalline form of the phosphate salt of form A from the suspension.
  • the method further comprises isolating the crystallized anhydrous crystalline form A.
  • the phosphoric acid contacted is present in an amount from about 1 equivalent to about 10 equivalents, from about 2 equivalents to about 9 equivalents, from about 3 equivalents to about 8 equivalents, or from about 4 equivalents to about 7 equivalents, with respect to the molar amount of the free base contacted. In other embodiments, the phosphoric acid contacted is present in an amount from about 2 equivalents to about 4 equivalents or at about 3 equivalents with respect to the molar amount of the free base contacted. In certain embodiments, the suspension of the free base and the phosphoric acid are reacted or contacted from about 2 h to about 40 h, from about 4 h to about 20 h, or from about 8 h to about 10 h.
  • the free base and the phosphoric acid are reacted at a temperature in the range of about 25° C. to about 100° C., about 40° C. to about 85° C., or about 55° C. to about 70° C.
  • the free base and the phosphoric acid are reacted at a temperature at which a solvent employed in the reaction refluxes.
  • the reaction is performed using reactants and one or more solvents that are substantially free of water (i.e., almost completely free of water).
  • the anhydrous crystalline form of the phosphate salt of form A obtained by the methods of the present technology may be further subjected to steps such as, e.g., drying, purification, etc.
  • the isolated crystals may be subjected to drying at a suitable temperature.
  • the crystals are dried at a temperature in the range of about 20° C. to about 80° C.
  • the crystals are dried at a temperature in the range of about 30° C. to about 70° C.
  • the crystals are dried at a temperature in the range of about 40° C. to about 60° C.
  • the crystals are dried under reduced pressure in the range, for example, of about 10 mbar-about 40 mbar.
  • the drying step may be conducted for a suitable period of time.
  • the crystals are dried for a period of about 1 to about 72 hours, from about 2 to about 36 hours or from about 4 to about 18 hours. In some embodiments, the crystals are dried for about 48 h.
  • the phosphate salt of the compound of Formula I may be used to prepare the monohydrate of the free base.
  • the phosphate salt may be dissolved in an aqueous solution of an inorganic base, such as aqueous ammonium hydroxide. Over time, the free base precipitates out as a crystalline monohydrate.
  • additional steps such as filtration, washing and drying may be used to isolate the crystalline free base monohydrate, just as the phosphate salt was isolated as described above.
  • Crystalline forms of the present technology may be isolated in substantially pure form.
  • substantially pure it is meant that more than 50% by weight of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl ⁇ -1-methyl-urea is present in one of the crystalline forms disclosed herein.
  • 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl ⁇ -1-methyl-urea is present at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the indicated form.
  • the present technology provides phosphate salts of the free base wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total phosphate salt of the free base is present as form A, form B or the amorphous form.
  • the present technology provides the free base such that at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total of the free base is present as the crystalline anhydrous free base, the crystalline monohydrate of the free base, or the amorphous form of the free base.
  • the present technology provides hydrochloride salts of the free base wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total is the amorphous or the crystalline dihydrate form of the hydrochloride salt.
  • compositions and medicaments which may be prepared by mixing one or more anhydrous or hydrated crystalline or amorphous forms (of, e.g., the free base, the phosphate salts or the hydrochloride salts thereof) of the present technology, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to treat certain diseases as described herein.
  • the present technology provides compositions comprising an anhydrous or hydrated crystalline form or an amorphous form of the present technology and a pharmaceutically acceptable carrier, excipient, and/or diluent.
  • the anhydrous crystal form is of the compound of Formula I as the free base.
  • the hydrated crystal form is the monohydrate of the compound of Formula I as the free base.
  • the anhydrous crystalline form is of the monophosphoric acid salt of the compound of Formula I.
  • the anhydrous crystalline form of the monophosphoric acid salt is of form A.
  • the anhydrous crystalline form of the monophosphoric acid salt is of form B.
  • the monophosphoric acid salt of the compound of Formula I is amorphous.
  • the form is of the hydrochloride salt of the compound of Formula I.
  • the hydrochloride salt is the crystalline dihydrate or the amorphous form.
  • compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the composition is substantially free of water.
  • the instant compositions can be formulated for various routes of administration, for example, by oral and parenteral administration.
  • Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections.
  • the following dosage forms are given by way of example and should not be construed as limiting the instant technology.
  • Injectable dosage forms generally include oil suspensions or aqueous suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. In certain embodiments, such aqueous injectable forms are prepared (or reconstituted) immediately before administration to the subject. Alternatively, sterile oils may be employed as solvents or suspending agents. Typically, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the pharmaceutical compositions and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the pharmaceutical compositions may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more anhydrous crystalline form of the present technology, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides.
  • a starch or other additive are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, ge
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
  • suitable coating materials known in the art.
  • Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
  • Pharmaceutical compositions and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents may be added for oral or parenteral administration.
  • the liquid dosage forms, particularly of the crystalline forms of the free base monophosphate salt are substantially free of water.
  • suspensions may include oils.
  • oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspensions of pharmaceutical compositions may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Ethers such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension pharmaceutical compositions.
  • excipients and carriers are generally known to those skilled in the art and are thus included in the present technology. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
  • compositions of the present technology may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below.
  • the pharmaceutical compositions may also be prepared for controlled release or for slow release.
  • compositions may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical compositions and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.
  • Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing therapeutically effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the present technology.
  • the present technology provides compositions comprising the free base of the compound of Formula I, wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total free base in the composition is present as the anhydrous form, or as the monohydrate form.
  • the compositions of the present technology consist essentially of the free base, where at least about 95%, at least about 97%, at least about 98%, or at least about 99% of the free base is present in the composition as the anhydrous form, or as the monohydrate form.
  • the present technology provides compositions comprising the phosphate salt of the free base wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total phosphate salt of the free base in the composition is present as form A, as form B, or as the amorphous form.
  • the compositions of the present technology consist essentially of a phosphate salt of the free base, where at least about 95%, at least about 97%, at least about 98%, or at least about 99% of the phosphate salt of the free base is present in the composition as form A, as form B, or as the amorphous form.
  • the present technology provides compositions comprising the hydrochloride salt of the free base wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% by weight of the total hydrochloride salt of the free base in the composition is present as the dihydrate, or as the amorphous form.
  • the compositions of the present technology consist essentially of a hydrochloride salt of the free base, where at least about 95%, at least about 97%, at least about 98%, or at least about 99% of the phosphate salt of the free base is present in the composition as the dihydrate, or as the amorphous form.
  • the present technology provides a method of treatment comprising administering a therapeutically effective amount of an anhydrous or hydrated crystalline form or an amorphous form or a composition comprising an anhydrous or hydrated crystalline form or amorphous form of the present technology to a subject suffering from a disease, the pathology and/or symptoms of which disease can be prevented, inhibited or ameliorated by inhibition of a kinase activity wherein the kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret.
  • the present technology provides the use of the anhydrous or hydrated crystalline forms, the amorphous forms or the compositions including the anhydrous or hydrated crystalline forms or amorphous forms of the present technology in the manufacture of a medicament for treating a disease in a subject wherein the kinase activity of FGFR1, FGFR2, FGFR3, FGFR4, KDR, HER1, HER2, Bcr-Abl, Tie2, and Ret contributes to the pathology and/or symptoms of the disease.
  • the kinase is selected from the group consisting of FGFR1, FGFR2, FGFR3, FGFR4.
  • Treatment within the context of the instant technology means an alleviation, in whole or in part, of symptoms associated with a disorder or disease, or slowing or halting of further progression or worsening of those symptoms, or tending to prevent or ward off the disease or disorder in a subject at risk for developing the disease or disorder.
  • diseases or disorders include, but are not limited to carcinoma of the kidneys, liver, adrenal glands, bladder, breast, stomach, ovaries, colon, rectum, prostate, pancreas, lungs, vagina or thyroid; sarcoma; glioblastoma; leukemia; tumors of the neck or head; psoriasis; prostate hyperplasia; or neoplasia.
  • a successful treatment may include an alleviation of symptoms or slowing or halting the progression of the disease, as measured by a reduction in levels or activity of one or more corresponding kinases.
  • a “therapeutically effective amount” refers to an amount of the anhydrous or hydrated crystalline form or amorphous form of the compound of Formula I (including the free base), or the anhydrous crystalline form or amorphous form of the phosphate salt of the compound of Formula I, they hydrochloride salt of the compound of Formula I (including the dihydrate or amorphous form) or compositions including them, that alleviates, in whole or in part, symptoms associated with the disorder or disease treated, or slows or halts of further progression or worsening of its symptoms, or prevents or provides prophylaxis for the disease or disorder in a subject at risk for developing the disease or disorder.
  • a subject is any animal that can benefit from the administration of any of the forms of the compound of Formula I or a composition including it, as disclosed herein.
  • the subject is a mammal, for example, a human, a primate, a dog, a cat, a horse, a cow, a pig, a rodent, such as for example a rat or mouse.
  • the mammal is a human.
  • a therapeutically effective amount of an anhydrous or hydrated crystalline form, or an amorphous form, or a composition comprising any such form of the present technology may vary depending upon the route of administration and dosage form.
  • Effective amounts of the anhydrous or hydrated crystalline forms or amorphous forms of the compounds of Formula I typically fall in the range of about 0.01 up to 100 mg/kg/day, and more typically in the range of about 0.05 up to 25 mg/kg/day.
  • the anhydrous or hydrated crystalline form, the amorphous form and the composition comprising such forms of the present technology are selected to provide pharmaceutical compositions that exhibit high therapeutic indices.
  • the therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD 50 and ED 50 .
  • the LD 50 is the dose lethal to 50% of the population and the ED 50 is the dose therapeutically effective in 50% of the population.
  • the LD 50 and ED 50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
  • the pH of a solution was determined as exemplified: approximately 10 mg of the free base or its salt was transferred to a 20 ml vial and 10 ml of the corresponding buffer or water added to it. The solution was stirred continuously as the pH was measured. pH measurement can be carried out by a variety of methods, such as, by using micro pH electrodes.
  • the intrinsic dissolution rate measurements were carried out in 0.5 cm 2 VanKel punch and die assemblies at a pellet pressure of 2000 pounds.
  • the dissolution was measured using fiber optics dissolution system (C technologies Inc.) and a Cary UV/VIS spectrophotometer, with a stirring rate of 200 rpm.
  • the solution medium was held at 37 ⁇ 0.5° C. and the concentration measurements were made at 260 nm.
  • Hygroscopicity was measured from sorption/desorption isotherms using Surface Measurement System DVS-1 at 25 ⁇ 0.5° C. Samples were evaluated at various humidities including 75%, 85%, and 95%.
  • Instrument TA instrument Q500; temperature range: room temperature to 300° C.; scan rate: 10° C./min; nitrogen flow: 60 ml/min. Mettler TGA 850; temperature range: room temperature to 300° C.; scan rate: 20° C./min; nitrogen flow: 40 ml/min.
  • Instrument TA instrument Q1000; temperature range: room temperature to 210° C.; scan rate: 10° C./min; nitrogen flow: 60 mL/min.
  • Instrument Thermo Magna 560; mode: transmission; scan range: 4000 cm ⁇ 1 -600 cm ⁇ 1 .
  • a salt screening experiment was performed with the free base of Formula I (prepared as described in Example 2 below) and a variety of different acids: acetic acid, benzoic acid, citric acid, fumaric acid, hippuric acid, hydrobromic acid, hydrochloric acid, lactic acid (D,L), maleic acid, malic acid (L), malonic acid, methanesulfonic acid, phosphoric acid, naphthalene-1,5-disulfonic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid (D), and tartaric acid (L).
  • the free base (30 mg) was dissolved in 12 mL THF.
  • the phosphate salt was found to be highly crystalline. Hygroscopicity as assessed by DVS sorption/desorption isotherms indicated that even at 95% RH, less than a 2% weight gain due to water absorption was observed. At 75% and 85% RH, less than a 1% weight gain was observed.
  • hydrochloride salt For the hydrochloride salt, several XRPD patterns were observed indicating the presence of more than one polymorph. Most of these salts had low crystallinity. The dihydrate was identified as the most crystalline. The hydrochloride salt was more hygroscopic than the phosphate salt. In one form of the hydrochloride salt, a weight gain of about 4.1% (75% RH) to about 16.9% (95% RH) was observed by DVS.
  • malonate salts For the malonate salts, four forms were identified based on their observed XRPD patterns. The one evaluated further, demonstrated a fragile crystal, was only made once, had a wet pattern, and was hygroscopic (about 10% weight gain at all humidities tested).
  • methane sulfonic acid (or mesylate) salt For the methane sulfonic acid (or mesylate) salt, several XRPD patterns were observed of which only one could be made consistently but it was hygroscopic (exhibiting about 2.6% to 10% weight gain by DVS). Similarly, the succinate salt was also hygroscopic (exhibiting about a 4.1% to 10% weight gain by DVS).
  • Results of an initial solubility test in pH 3 buffer and in water are shown below in Table 1.
  • the phosphate salt was more soluble than the methanesulfonate, malonate, and succinate salts in pH 3 buffer and in water.
  • the phosphate salt was also more soluble in water than the free base.
  • a mixture of 1-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1-ethylpiperazine (7.6 ml, 59.4 mmol, 2 eq.) is heated to 80° C. for 15 h. After cooling to RT, the reaction mixture is diluted with water and DCM/MeOH, 9:1. The aqueous layer is separated and extracted with DCM/MeOH, 9:1. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated.
  • the title compound was prepared by adding 2,6-dichloro-3,5-dimethoxyphenyl-isocyanate (1.25 eq.) to a solution of N-[4-(4-ethyl-piperazin-1-yl)-phenyl]-N′-methyl-pyrimidine-4,6-diamine (2.39 g, 7.7 mmol, 1 eq.) in toluene and stirring the reaction mixture for 1.5 h at reflux.
  • the solid was filtered through a 3 L coarse frit sintered glass funnel with a coarse frit (40-60 ASTM). The filter cake was rinsed with deionized water (2 L). The solid was dried at 60° C. under vacuum (5 torr) for 16 hours to give the free base as a monohydrate (559 g, 96.7% of theory for a monohydrate).
  • the anhydrous free base showed good crystallinity (for XRPD spectrum, see FIG. 1A ). It was slightly hygroscopic, and upon heating at 10° C./min, melted at 217° C. (onset) with subsequent decomposition (for DSC thermogram, see FIG. 2A ).
  • the TGA for the anhydrous base is shown in FIG. 3A , and the observed weight loss is consistent with the anhydrous form. It was not soluble in aqueous media at high pH (ca. 0.00004 mg/mL in pH 6.8 buffer and ca 0.00009 mg/mL with pH 6.67 in water), and sparingly to slightly soluble in common organic solvents.
  • anhydrous free base changes into another form (likely a form of hydrochloride).
  • the monohydrate form of the free base also showed good crystallinity (for XRPD spectrum, see FIG. 1D ).
  • An SEM micrograph of the anhydrous free base is shown in FIG. 5A .
  • the phosphate salt showed good crystallinity (for XRPD spectrum, see FIG. 1B (phosphate salt (form A)). It was slightly hygroscopic, and upon heating at 10° C./min, melted at 184.0° C. (onset) with subsequent decomposition (See FIG. 2B (phosphate salt (form A)).
  • the TGA of the phosphate salt is shown in FIG. 3B , and the observed weight loss is consistent with the anhydrous form. It was not soluble in pH 6.8 buffer (ca. 0.00009 mg/mL), but, unlike the free base, was soluble in water (1.3 mg/mL). It was sparingly soluble in common organic solvents. Additional solubility studies are presented below.
  • the FT-IR spectrum of the phosphate salt (form A) is shown in FIG. 6 . Up to 0.6% of residual solvent (isopropanol) was detected in the phosphate salt.
  • An SEM micrograph of the phosphate salt, form A is shown in FIG. 5B .
  • the hydrochloride salt showed moderate crystallinity (for XRPD spectrum, see FIG. 1E ) in the dihydrate form.
  • the TGA is shown in FIG. 3C , and the observed weight loss is consistent with the dihydrate form.
  • the hydrochloride is hygroscopic and the present form is a dihydrate. Solubility studies are presented in Example 8, Table 3D.
  • phosphate salt (form A) was mixed with 4 ml of tetrahydrofuran/water (1:1) at 25° C. After stirring overnight, the solution was filtered. With no stirring, the clear filtrate was placed under nitrogen flow to dry. The solid, obtained after solvent evaporation, was further evaluated by DSC and TGA. No apparent glass transition was observed on DSC thermograph when subjected to heating from ⁇ 40° C. to 140° C. On TGA thermograph, it was observed that the sample started to decompose at ⁇ 115° C., much lower than the form A of the crystalline phosphate salt. See also Example 15, below.
  • the measurements were carried out on a VanKel instrument using a Cary UV/VIS spectrophotometer (Table 2).
  • the phosphate salt demonstrated faster intrinsic dissolution rates in water and 0.1N HCl than the free base.
  • Solubility of the monohydrate of the anhydrous and monohydrate free base was measured in various aqueous media (e.g., pH 6.8 buffer, pH 4.5 buffer, pH 1 buffer), including simulated and actual human fluids.
  • aqueous media e.g., pH 6.8 buffer, pH 4.5 buffer, pH 1 buffer
  • the simulated fluid compositions are shown in table 3A-3C below.
  • the human fluids were collected from 12 human subjects. The solubility was assessed as described above after 24 hours. Results are tabulated below in Tables 4A and 4B.
  • Peaks in FIG. 8A include 3067, 2950, 2927, 2854, 2828, 1690, 1619, 1585, 1539, 1458, 1409, 1385, 1358, 1297, 1233, 1191, 1098, 1062, 998, 819, 778, 742, 695, 668, 637, 498, 468, 420 cm ⁇ 1 .
  • the Raman spectrum for the monohydrate free base is shown in FIG. 8B . Peaks in FIG. 8B include 2957, 2831, 1618, 1580, 1511, 1465, 1415, 1361, 1312, 1284, 1229, 1186, 1148, 1057, 994, 854, 721, 661, 624 cm ⁇ 1 .
  • the solution stability of the free base was tested in buffers ranging from pH 1 to pH 9 for 1 week at 50° C. At pH 5 and higher, the free base was stable, and after accounting for minor initial impurities, degradation was less than 2%. At pH 3, degradation was about 4% and at pH 1, degradation was about 15%. The stability was also tested in water and several organic solvents (1 week at 50° C.). The free base was stable in isopropanol and showed from about 6 to 7% degradation in acetonitrile and methanol.
  • the phosphate salt, form A was stable in isopropanol and acetonitrile, and showed about 8% degradation in methanol.
  • the free base was stable, but the phosphate salt showed about 45% degradation. This does not impact the administration of the phosphate salt orally; in fact, as demonstrated below, the phosphate salt has about a 2-fold higher bioavailability than the free base.
  • the stability difference between the free base and phosphate salt may be due to the higher aqueous solubility of the phosphate salt compared to the free base, as well as the tendency of the phosphate salt to cause the pH of water to decrease, which may increase the rate of degradation.
  • Both the free base and phosphate salt showed the highest degradation in 1:1 acetonitrile/water (about 8% and 70%, respectively).
  • the samples were stressed for one week at 80° C., in sealed containers and under 75% relative humidity.
  • the crystal forms of the anhydrous free base and the phosphate salt (form A) were demonstrated to be stable in the solid state, alone, and in presence of excipients as a 1% mixture.
  • the amount of degradation products of the anhydrous free base as assessed by HPLC was 1% or less (based on peak area), while the degradation of the phosphate salt accounted for 1.4% or less.
  • the XRPD of each polymorph showed no change of form.
  • the free base was equilibrated in water, ethanol, isopropanol, ethyl acetate, and acetone, and as above, analyzed by XRPD. No new XRPD pattern was observed.
  • the phosphate salt (form A) was dissolved in DMSO where its solubility was high.
  • a solvent (the anti-solvent) in which the form A was highly insoluble was added to the solution.
  • the precipitate was collected on a filter, dried, and investigated by XRPD. No change in Form was observed for any of the following solvents: methanol, ethanol, isopropanol, acetone, acetonitrile, THF, ethyl acetate, propyl acetate, toluene, methyl t-butyl ether, 1,4-dioxane, methylene chloride.
  • the phosphate salt (form A, 300 mg) was compressed for 5 minutes at 4000 pounds with a hydraulic press (diameter of the tablets 8 mm). No change of crystalline modification was observed by XRPD. These results demonstrated the stability of the crystalline form of the phosphate salt (form A).
  • a solvent water or ethanol was added drop wise to the phosphate salt (form A) placed in a mortar until the solid in the mortar was sufficiently wet, and ground using a pestle until a paste-like consistency was obtained.
  • the paste was dried at around 40° C. and under reduced pressure for >8 hours.
  • the solids were evaluated by XRPD, and no changes in the XRPD spectra were observed. These results demonstrated the stability of the crystalline form of the phosphate salt (form A).
  • FIGS. 3A (free base) and 3 B (phosphate salt (form A)) shows the water sorption-desorption isotherm recorded on a TGA instrument.
  • the DVS plots are shown in FIGS. 4A (free base, anhydrous), 4 B (phosphate salt (form A) and 4 C (free base, monohydrate).
  • the maximum water uptake for the phosphate salt (form A) was less than 2% (i.e. 0.7%) at 25° C. up to 95% relative humidity (rh) (see Table 9).
  • the maximum water uptake for the monohydrate was less than 1.4% at 25° C. up to 95% RH.
  • the monohydrate with an approximate water content of 3% could not be completely dried during the experiment but the water that could be removed was reversibly reabsorbed.
  • the plateau of existence of the monohydrate form is found to be within 10% and 95% RH with a slight hysteresis at the second desorption cycle.
  • the phosphate salt was prepared as follows. In a glass vial, 10.7 mg of the free base was dissolved in 4 ml THF. Phosphoric acid (1.76 ml) in acetone (0.01M) was added. The mixture was warmed to 50° C. for about 2 minutes. The vial was left open for partial evaporation at room temperature. Overnight, a suspension was formed, which was filtered yielding about 5.5 mg of an off-white powder.
  • the bioavailabilities, in rats, of the active agents (the free base and its phosphate salt), formulated variously, are tabulated below (Table 10).
US13/514,308 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl) -phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof Active 2031-02-24 US9067896B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/514,308 US9067896B2 (en) 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl) -phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US26715509P 2009-12-07 2009-12-07
PCT/US2010/059108 WO2011071821A1 (fr) 2009-12-07 2010-12-06 Formes cristallines de la 3-(2,6-dichloro-3,5-diméthoxy-phényl)-1-{6-[4-(4-éthyl-pipérazin-1-yl)-phénylamino]-pyrimidin-4-yl}-1-méthyl-urée et de ses sels
US13/514,308 US9067896B2 (en) 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl) -phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof

Publications (2)

Publication Number Publication Date
US20120245182A1 US20120245182A1 (en) 2012-09-27
US9067896B2 true US9067896B2 (en) 2015-06-30

Family

ID=43983750

Family Applications (1)

Application Number Title Priority Date Filing Date
US13/514,308 Active 2031-02-24 US9067896B2 (en) 2009-12-07 2010-12-06 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl) -phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof

Country Status (32)

Country Link
US (1) US9067896B2 (fr)
EP (1) EP2509963B1 (fr)
JP (2) JP5714024B2 (fr)
KR (1) KR101787784B1 (fr)
CN (5) CN111269186A (fr)
AR (2) AR079257A1 (fr)
AU (1) AU2010328391B2 (fr)
CA (1) CA2781431C (fr)
CL (1) CL2012001480A1 (fr)
DK (1) DK2509963T3 (fr)
EC (1) ECSP12012026A (fr)
ES (1) ES2562462T3 (fr)
GT (1) GT201200181A (fr)
HK (1) HK1171016A1 (fr)
HR (1) HRP20160126T1 (fr)
HU (1) HUE026983T2 (fr)
IL (1) IL220012B (fr)
JO (1) JO3061B1 (fr)
MA (1) MA33849B1 (fr)
MX (1) MX2012006562A (fr)
MY (1) MY158333A (fr)
NZ (3) NZ700778A (fr)
PE (1) PE20121499A1 (fr)
PH (1) PH12014502593A1 (fr)
PL (1) PL2509963T3 (fr)
RU (1) RU2572848C2 (fr)
SG (1) SG10201408063SA (fr)
SI (1) SI2509963T1 (fr)
TN (1) TN2012000263A1 (fr)
TW (1) TWI526440B (fr)
WO (1) WO2011071821A1 (fr)
ZA (1) ZA201203612B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9321786B2 (en) 2013-03-15 2016-04-26 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9663524B2 (en) 2013-03-15 2017-05-30 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as protein kinase inhibitors
US10065966B2 (en) 2013-03-15 2018-09-04 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US11160804B2 (en) 2013-12-13 2021-11-02 Novartis Ag Pharmaceutical dosage forms

Families Citing this family (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0512324D0 (en) * 2005-06-16 2005-07-27 Novartis Ag Organic compounds
AR079257A1 (es) * 2009-12-07 2012-01-04 Novartis Ag Formas cristalinas de 3-(2,6-dicloro-3-5-dimetoxi-fenil)-1-{6-[4-(4-etil-piperazin-1-il)-fenil-amino]-pirimidin-4-il}-1-metil-urea y sales de las mismas
WO2012088266A2 (fr) 2010-12-22 2012-06-28 Incyte Corporation Imidazopyridazines et benzimidazoles substitués en tant qu'inhibiteurs de fgfr3
CN109718239A (zh) * 2012-03-30 2019-05-07 诺华股份有限公司 用于治疗低磷血性疾病的fgfr抑制剂
BR112014030812B1 (pt) 2012-06-13 2022-11-08 Incyte Holdings Corporation Compostos tricíclicos substituídos como inibidores de fgfr, seus usos, composição farmacêutica e método para inibir uma enzima fgfr
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
AR094812A1 (es) 2013-02-20 2015-08-26 Eisai R&D Man Co Ltd Derivado de piridina monocíclico como inhibidor del fgfr
WO2014155268A2 (fr) 2013-03-25 2014-10-02 Novartis Ag Inhibiteurs de kinase tyrosine fgf-r et leur utilisation dans le traitement de maladies associées à un manque ou à une absence d'activité snf5
SG10201708520YA (en) 2013-04-19 2017-12-28 Incyte Corp Bicyclic heterocycles as fgfr inhibitors
JP2016523973A (ja) * 2013-07-09 2016-08-12 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド 疾患の処置のためのキナーゼ阻害物質
CN105899490B (zh) * 2013-10-18 2019-07-23 卫材R&D管理有限公司 嘧啶fgfr4抑制剂
US9951047B2 (en) 2014-08-18 2018-04-24 Eisai R&D Management Co., Ltd. Salt of monocyclic pyridine derivative and crystal thereof
WO2016055916A1 (fr) 2014-10-06 2016-04-14 Novartis Ag Combinaison thérapeutique pour le traitement du cancer
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
WO2016134294A1 (fr) 2015-02-20 2016-08-25 Incyte Corporation Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
MA41551A (fr) 2015-02-20 2017-12-26 Incyte Corp Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
AU2016219822B2 (en) 2015-02-20 2020-07-09 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
WO2016151501A1 (fr) 2015-03-25 2016-09-29 Novartis Ag Combinaisons pharmaceutiques
US10562888B2 (en) 2015-04-14 2020-02-18 Eisai R&D Management Co., Ltd. Crystalline FGFR4 inhibitor compound and uses thereof
CN104803925B (zh) * 2015-04-16 2018-01-12 温州医科大学 一类以fgfr为靶点的2，4，5‑三取代嘧啶类化合物及其制备方法和用途
WO2016189472A1 (fr) 2015-05-28 2016-12-01 Novartis Ag Inhibiteur de fgfr destiné à être utilisé dans le traitement de la tumeur mésenchymateuse phosphaturique
WO2017196854A1 (fr) 2016-05-10 2017-11-16 Eisai R&D Management Co., Ltd. Associations médicamenteuses permettant de réduire la viabilité et/ou la prolifération cellulaire
TWI669300B (zh) * 2016-05-20 2019-08-21 浙江海正藥業股份有限公司 嘧啶類衍生物、其製備方法、其藥物組合物以及其在醫藥上的用途
CA3034875A1 (fr) * 2016-08-23 2018-03-01 Eisai R&D Management Co., Ltd. Polytherapies pour le traitement du carcinome hepatocellulaire
AR111960A1 (es) 2017-05-26 2019-09-04 Incyte Corp Formas cristalinas de un inhibidor de fgfr y procesos para su preparación
CN107176954B (zh) 2017-06-02 2019-01-11 无锡双良生物科技有限公司 一种egfr抑制剂的药用盐及其晶型、制备方法和应用
AU2018361264B2 (en) * 2017-11-01 2021-04-01 Guangdong Xianqiang Pharmaceutical Co., Ltd Salt form and crystal form of compound as FGFR4 inhibitor and preparation method thereof
BR112020017922A2 (pt) 2018-03-28 2020-12-22 Eisai R&D Management Co., Ltd. Agente terapêutico para carcinoma hepatocelular
SG11202010882XA (en) 2018-05-04 2020-11-27 Incyte Corp Salts of an fgfr inhibitor
KR20210018265A (ko) 2018-05-04 2021-02-17 인사이트 코포레이션 Fgfr 억제제의 고체 형태 및 이의 제조 방법
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
JP2022552324A (ja) 2019-10-14 2022-12-15 インサイト・コーポレイション Ｆｇｆｒ阻害剤としての二環式複素環
WO2021076728A1 (fr) 2019-10-16 2021-04-22 Incyte Corporation Hétérocycles bicycliques en tant qu'inhibiteurs de fgfr
CA3163875A1 (fr) 2019-12-04 2021-06-10 Incyte Corporation Heterocycles tricycliques en tant qu'inhibiteurs de fgfr
EP4069695A1 (fr) 2019-12-04 2022-10-12 Incyte Corporation Dérivés d'un inhibiteur de fgfr
AR126102A1 (es) 2021-06-09 2023-09-13 Incyte Corp Heterociclos tricíclicos como inhibidores de fgfr
US11583602B2 (en) 2021-06-23 2023-02-21 Kimtron, Inc. System and method for ultra-close proximity irradiation of rotating biomass
WO2023174400A1 (fr) * 2022-03-18 2023-09-21 上海润石医药科技有限公司 Sel de composé hétérocyclique nitrique à six chaînons amino substitué, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée
CN115785001B (zh) * 2022-11-23 2023-09-15 斯坦德药典标准物质研发(湖北)有限公司 一种英菲格拉替尼的制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006000420A1 (fr) 2004-06-24 2006-01-05 Novartis Ag Derives pyrimidines uree en tant qu'inhibiteurs de kinase
WO2007071752A2 (fr) 2005-12-21 2007-06-28 Novartis Ag Derives pyrimidinyl-aryluree constituant des inhibiteurs des facteurs de croissance des fibroblastes (fgf)
US8293743B2 (en) * 2005-11-08 2012-10-23 Choongwae Pharma Corporation Substituted imidazo[1,2-A]pyrazine derivatives as alpha-helix mimetics and method relating to the treatment of cancer stem cells

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101242843A (zh) * 2005-06-10 2008-08-13 詹森药业有限公司 作为激酶调节剂的氨基嘧啶类化合物
BRPI0911491A2 (pt) * 2008-04-29 2016-01-05 Novartis Ag métodos de monitoramento da modulação de atividade de quinase de receptor de fator de crescimento de fibroblasto e usos dos ditos métodos.
AR079257A1 (es) * 2009-12-07 2012-01-04 Novartis Ag Formas cristalinas de 3-(2,6-dicloro-3-5-dimetoxi-fenil)-1-{6-[4-(4-etil-piperazin-1-il)-fenil-amino]-pirimidin-4-il}-1-metil-urea y sales de las mismas

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006000420A1 (fr) 2004-06-24 2006-01-05 Novartis Ag Derives pyrimidines uree en tant qu'inhibiteurs de kinase
US8293743B2 (en) * 2005-11-08 2012-10-23 Choongwae Pharma Corporation Substituted imidazo[1,2-A]pyrazine derivatives as alpha-helix mimetics and method relating to the treatment of cancer stem cells
WO2007071752A2 (fr) 2005-12-21 2007-06-28 Novartis Ag Derives pyrimidinyl-aryluree constituant des inhibiteurs des facteurs de croissance des fibroblastes (fgf)
US20080312248A1 (en) * 2005-12-21 2008-12-18 Novartis Ag Pyrimidinyl Aryl Urea Derivatives Being Fgf Inhibitors

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
Bavin, Mike et al., "Process Development-Polymorphism in Process Development", Chemistry & Industry No. 16, pp. 527-529, Aug. 21, 1989.
Byrn S. et al., "Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations", Pharmaceutical Research, vol. 12, No. 7, p. 945-954, (1995).
D. J. W. Grant and J. K. Guillory, "Polymorphism in pharmaceutical solids" edited by H. G. Brittain, Marcel Dekker, D. J. W. Grant (chapter 1) p. 1-10; and J. K. Guillory (chapter 5) p. 183-226, 1999.
Gennaro, Alfonso R., Remington, The Science and Practice of Pharmacy, 17th Ed., pp. 1912-1920, 1985.
Haynes D. A. et al., "Occurrence of Pharmaceutically Acceptable Anions and Cations in the Cambridge Database", Journal of Pharmaceutical Sciences, vol. 94, No. 10, p. 2111-2120, (2005).
Mino R. Caria, "Crystalline Polymorphism of Organic Compounds", Topic in Current Chemistry, vol. 198, p. 163-208, (1998).
Mitsuru Hashida, "Formulation Design and Evaluation of Oral Dosage Form", Yakugyo Jiho Co.Ltd., pp. 76-79 and 171-172, Feb. 10, 1995 [English Translation].
Sashin Souyaku, "The Practice of Medical Chemistry", Last Volume (Japanese Edition), pp. 347-365, Sep. 25, 1999 [English Translation].
Teruzo Asahara et al., "Solvent Handbook", Kodansha Ltd., pp. 47-51, Sep. 1, 1985 [English Translation].

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9321786B2 (en) 2013-03-15 2016-04-26 Celgene Avilomics Research, Inc. Heteroaryl compounds and uses thereof
US9663524B2 (en) 2013-03-15 2017-05-30 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as protein kinase inhibitors
US9695132B2 (en) 2013-03-15 2017-07-04 Celgene Car Llc Heteroaryl compounds and uses thereof
US10065966B2 (en) 2013-03-15 2018-09-04 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US10189794B2 (en) 2013-03-15 2019-01-29 Celgene Car Llc Heteroaryl compounds and uses thereof
US10618902B2 (en) 2013-03-15 2020-04-14 Celgene Car Llc Substituted pyrido[2,3-d]pyrimidines as inhibitors of protein kinases
US10774052B2 (en) 2013-03-15 2020-09-15 Celgene Car Llc Heteroaryl compounds and uses thereof
US11160804B2 (en) 2013-12-13 2021-11-02 Novartis Ag Pharmaceutical dosage forms

Also Published As

Publication number Publication date
CL2012001480A1 (es) 2014-09-05
NZ624315A (en) 2014-11-28
AR079257A1 (es) 2012-01-04
EP2509963A1 (fr) 2012-10-17
PE20121499A1 (es) 2012-11-15
CA2781431C (fr) 2017-10-31
KR20130028045A (ko) 2013-03-18
HK1171016A1 (zh) 2013-03-15
HUE026983T2 (en) 2016-08-29
NZ700778A (en) 2015-04-24
CN111100077A (zh) 2020-05-05
RU2572848C2 (ru) 2016-01-20
KR101787784B1 (ko) 2017-10-18
MY158333A (en) 2016-09-30
JP2013512956A (ja) 2013-04-18
SG10201408063SA (en) 2015-01-29
IL220012A0 (en) 2012-07-31
JO3061B1 (ar) 2017-03-15
BR112012013784A8 (pt) 2017-12-26
ZA201203612B (en) 2013-01-30
DK2509963T3 (en) 2016-02-29
CN102639510A (zh) 2012-08-15
AU2010328391A1 (en) 2012-06-07
JP6019142B2 (ja) 2016-11-02
PL2509963T3 (pl) 2016-05-31
SI2509963T1 (sl) 2016-05-31
CN105061332A (zh) 2015-11-18
ECSP12012026A (es) 2012-08-31
AU2010328391B2 (en) 2014-07-03
NZ600070A (en) 2014-06-27
EP2509963B1 (fr) 2015-11-25
PH12014502593A1 (en) 2015-09-21
MX2012006562A (es) 2012-07-04
TN2012000263A1 (en) 2013-12-12
JP5714024B2 (ja) 2015-05-07
TWI526440B (zh) 2016-03-21
RU2012128351A (ru) 2014-01-20
CN111100078A (zh) 2020-05-05
AR114946A2 (es) 2020-11-11
HRP20160126T1 (hr) 2016-03-25
MA33849B1 (fr) 2012-12-03
WO2011071821A1 (fr) 2011-06-16
CA2781431A1 (fr) 2011-06-16
TW201144297A (en) 2011-12-16
IL220012B (en) 2018-02-28
CN111269186A (zh) 2020-06-12
BR112012013784A2 (pt) 2016-05-03
ES2562462T3 (es) 2016-03-04
JP2015107996A (ja) 2015-06-11
US20120245182A1 (en) 2012-09-27
GT201200181A (es) 2013-12-03

Similar Documents

Publication Publication Date Title
US9067896B2 (en) Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl) -phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof
US9309229B2 (en) Crystalline forms of 5-chloro-N2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2, 4-diamine
US10640487B2 (en) Solid state forms of Nilotinib salts
AU2014221268A1 (en) Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl) -1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino] -pyrimidin-4-yl}-1-methyl-urea and salts thereof.
BR112012013784B1 (pt) Formas cristalinas de 3-(2,6-dicloro-3,5-dimetoxi fenil)-1-{6-[4-(4-etil piperazin-1-il) fenil amino] pirimidin-4-il}-1-metil uréia, seus sais, seu uso e seu método de preparação, e composição

Legal Events

Date Code Title Description
AS Assignment

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BERGHAUSEN, JOERG;KAPA, PRASAD KOTESWARA;MCKENNA, JOSEPH;AND OTHERS;SIGNING DATES FROM 20110125 TO 20110207;REEL/FRAME:028625/0932

STCF Information on status: patent grant

Free format text: PATENTED CASE

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 8